© 2000 Oxford University Press
Human Molecular Genetics, 2000, Vol. 9, No. 18 2751–2760
Surfactant proteins A and B as interactive genetic determinants of neonatal respiratory distress syndrome Ritva Haataja1, Mika Rämet1,2, Riitta Marttila1 and Mikko Hallman1,+ 1Department 2Laboratory
of Paediatrics and Biocenter Oulu, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland and of Developmental Immunology, Massachussetts General Hospital, Boston, MA, USA
Received 4 August 2000; Revised and Accepted 8 September 2000
Prematurity is the most important risk factor predisposing to neonatal respiratory distress syndrome (RDS). Genetic factors are likely to contribute to the risk of this complex disease. The present study was designed to investigate whether the surfactant protein B (SP-B) gene or interaction between the SP-A and SP-B genes has a role in the genetic susceptibility to RDS. The genotype analyses were performed on 684 prematurely born neonates, of whom 184 developed RDS. Of the two SP-B polymorphisms genotyped, the Ile131Thr variation affects a putative N-terminal Nlinked glycosylation site of proSP-B and the length variation of intron 4 has previously been suggested to associate with RDS. Neither of the two SP-B polymorphisms associated directly with RDS or with prematurity. Instead, our data show that the previously identified association between SP-A alleles and RDS was dependent on the SP-B Ile131Thr genotype. On the basis of χ2 and logistic regression analyses, the SP-A allele, haplotype and genotype distributions differed significantly between the RDS infants and controls only when the SP-B genotype was Thr/Thr. Among the infants born before 32 weeks of gestation and having the SP-B genotype Thr/Thr, the SP-A1 allele 6A2 was over-represented in RDS group compared with controls (P = 0.001, OR = 4.7, CI 1.8– 12.2). In the same comparison, the SP-A1 allele 6A3 was under-represented in RDS (P = 0.001, OR = 0.2, CI 0.1–0.6). We propose that the SP-B Ile131Thr polymorphism is a determinant for certain SP-A alleles as factors causing genetic susceptibility to RDS (6A2, 1A0) or protection against it (6A3, 1A2). INTRODUCTION Neonatal respiratory distress syndrome (RDS) is the major cause of mortality and morbidity in premature infants. The disease is characterized by respiratory failure and deficient gas exchange. It is caused by a deficiency of pulmonary surfactant, a complex lipoprotein mixture produced by type II alveolar +To
epithelial cells (1–4). The main function of the surfactant is to stabilize the alveoli throughout the respiratory cycle, thus preventing alveolar collapse at the end of expiration (5). Surfactant is composed of ∼90% phospholipids and 10% surfactant proteins (SP-A, SP-B, SP-C and SP-D) (6). The incidence of RDS has decreased significantly due to prophylactic antenatal glucocorticoid treatment (7). Prematurity is the most important factor predisposing to RDS and race and gender additionally contribute to the risk of the disease (8,9). Furthermore, as suggested on the basis of a twin study and some other epidemiologic reports, genetic factors are assumed to have a role in the aetiology of RDS (10–12). However, the specific genes underlying this susceptibility are incompletely known. The most promising candidates studied so far are the genes coding for the lung-specific protein components of the surfactant, especially those coding for SP-A and SP-B (13,14). On the whole, the aetiology of RDS is considered multifactorial and possibly multigenic. The major surfactant protein, SP-A, is a hydrophilic collagenlike lectin that improves the surface activity of the surfactant complex and has a role in pulmonary host defence (15–17). Surprisingly, SP-A deficiency does not result in respiratory failure in newborn mice (18). The human SP-A is encoded by two highly homologous genes (SP-A1 and SP-A2) each spanning ∼5 kb in chromosome 10q22–q23 (19) and both genes are needed for fully functional mature SP-A protein (19–21). Several alleles that differ by a single amino acid have been identified for each SP-A gene (22–24). An association of SP-A alleles with the risk of RDS was recently reported among premature Finnish infants (25). SP-B is a lung epithelial cell-specific secreted hydrophobic protein, which has an essential role in normal lung function (6,26,27). It accelerates the rate of adsorption and spreading of surfactant phospholipids into the air–liquid interface. SP-B mRNA appears as early as the 14th gestational week in the human fetal lung (28) and after 25 weeks of gestation SP-B mRNA and protein are co-localized in terminal airways and type II epithelial cells (27,29). In human neonates, hereditary SP-B deficiency caused by a frameshift mutation 121ins2 results in a fatal respiratory disease known as congenital alveolar proteinosis (30). Targeted disruption of the SP-B gene leads to neonatal death due to severe respiratory failure in homozygous SP-B–/– mice (31).
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2752 Human Molecular Genetics, 2000, Vol. 9, No. 18
Table 1. Characteristics of the infants with RDS and the premature controls
Gestational age
(weeks)a
RDS
No RDS
30.3 ± 3.3
34.1 ± 2.3
Motif no. Motif sequence
(CA)n
1
(CA)14, variable
Birth weight (g)b
1539 ± 688
2241 ± 639
Male sex (n)
119
258
Female sex (n)
69
242
Prenatal glucocorticoid (n)
